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Eunice Kennedy Shriver National Institute of Child Health and Human Development - Program in Cellular Regulation and Metabolism
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Mary Dasso

Mary Dasso's Section on Cell Cycle Regulation uses a variety of metazoan systems, including Xenopus laevis egg extracts, to study mitotic roles of the Ran GTPase, the nuclear pore complex (NPC) and the SUMO family of ubiquitin-like proteins.

These pathways work in an interconnected manner to assure the accurate segregation of chromosomes during mitosis. In the past year, members of the group documented novel roles for both the SUMO pathway and NPC components in the assembly and function of mitotic kinetochores. Particularly the latter aspects of kinetochore function are regulated through Ran.

Publications

SUMOylation of the C-terminal domain of DNA topoisomerase II╬▒ regulates the centromeric localization of Claspin.

SUMOylation of the C-terminal domain of DNA topoisomerase IIα regulates the centromeric localization of Claspin.

Cell Cycle. 2015 Jul 1;:0

Authors: Ryu H, Yoshida MM, Sridharan V, Kumagai A, Dunphy WG, Dasso M, Azuma Y

Abstract
DNA topoisomerase II (TopoII) regulates DNA topology by its strand passaging reaction, which is required for genome maintenance by resolving tangled genomic DNA. In addition, TopoII contributes to the structural integrity of mitotic chromosomes and to the activation of cell cycle checkpoints in mitosis. Post-translational modification of TopoII is one of the key mechanisms by which its broad functions are regulated during mitosis. SUMOylation of TopoII is conserved in eukaryotes and plays a critical role in chromosome segregation. Using Xenopus laevis egg extract, we demonstrated previously that TopoIIα is modified by SUMO on mitotic chromosomes and that its activity is modulated via SUMOylation of its lysine at 660. However, both biochemical and genetic analyses indicated that TopoII has multiple SUMOylation sites in addition to Lys660, and the functions of the other SUMOylation sites were not clearly determined. In this study, we identified the SUMOylation sites on the C-terminal domain (CTD) of TopoIIα. CTD SUMOylation did not affect TopoIIα activity, indicating that its function is distinct from that of Lys660 SUMOylation. We found that CTD SUMOylation promotes protein binding and that Claspin, a well-established cell cycle checkpoint mediator, is one of the SUMOylation-dependent binding proteins. Claspin harbors two SUMO-interacting motifs (SIMs), and its robust association to mitotic chromosomes requires both the SIMs and TopoIIα-CTD SUMOylation. Claspin localizes to the mitotic centromeres depending on mitotic SUMOylation, suggesting that TopoIIα-CTD SUMOylation regulates the centromeric localization of Claspin. Our findings provide a novel mechanistic insight regarding how TopoIIα-CTD SUMOylation contributes to mitotic centromere activity.

PMID: 26131587 [PubMed - as supplied by publisher]

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